3.-Enfermedad Celiaca

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Issue date: May 2009

NICE clinical guideline 86Developed by the Centre for Clinical Practice at NICE

Coeliac diseaseRecognition and assessment of coeliacdisease


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NICE clinical guideline 86Coeliac disease: recognition and assessment of coeliac disease

Ordering information

You can download the following documents from www.nice.org.uk/CG86 The full guideline (this document) all the recommendations, details of how

they were developed, and reviews of the evidence they were based on.

A quick reference guide a summary of the recommendations forhealthcare professionals.

Understanding NICE guidance a summary for patients and carers.

For printed copies of the quick reference guide or Understanding NICEguidance, phone NICE publications on 0845 003 7783 or [email protected] and quote:

N1859 (quick reference guide)

N1860 (Understanding NICE guidance).

NICE clinical guidelines are recommendations about the treatment and care ofpeople with specific diseases and conditions in the NHS in England andWales.

This guidance represents the view of NICE, which was arrived at after carefulconsideration of the evidence available. Healthcare professionals areexpected to take it fully into account when exercising their clinical judgement.

However, the guidance does not override the individual responsibility ofhealthcare professionals to make decisions appropriate to the circumstancesof the individual patient, in consultation with the patient and/or guardian orcarer, and informed by the summary of product characteristics of any drugsthey are considering.

Implementation of this guidance is the responsibility of local commissionersand/or providers. Commissioners and providers are reminded that it is theirresponsibility to implement the guidance, in their local context, in light of theirduties to avoid unlawful discrimination and to have regard to promotingequality of opportunity. Nothing in this guidance should be interpreted in a way

that would be inconsistent with compliance with those duties.

National Institute for Health and Clinical Excellence

MidCity Place71 High HolbornLondon WC1V 6NA

www.nice.org.uk

National Institute for Health and Clinical Excellence, 2009. All rights reserved. This materialmay be freely reproduced for educational and not-for-profit purposes. No reproduction by orfor commercial organisations, or for commercial purposes, is allowed without the express

written permission of NICE.


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NICE clinical guideline 86 Coeliac disease 3

Contents

Disclaimer ....................................................................................................... 4Foreword ........................................................................................................ 5Patient-centred care ...................................................................................... 71 Summary .................................................................................................. 9

1.1 Recommendations ............................................................................. 91.2 Care pathway .................................................................................. 141.3 Overview .......................................................................................... 18

2 Evidence review .................................................................................... 202.1 Introduction ...................................................................................... 202.2 Prevalence of coeliac disease ......................................................... 212.3 The possible long-term consequences of undiagnosed coeliac

disease ........................................................................................... 232.4 Signs and symptoms of coeliac disease and coexisting conditions

with coeliac disease ......................................................................... 262.5 Serological tests in the diagnostic process for coeliac disease ....... 372.6 Research recommendations ............................................................ 59

3 References, glossary and abbreviations ............................................. 613.1 References ...................................................................................... 613.2 Glossary .......................................................................................... 713.3 Abbreviations ................................................................................... 74

4 Methods.................................................................................................. 744.1 Aim and scope of the guideline ........................................................ 744.2 Development methods ..................................................................... 74

5

Contributors ........................................................................................... 79

5.1 The Guideline Development Group ................................................. 795.2 Declarations ..................................................................................... 86

The appendices are available as separate files.

Appendix 6.1 Scope

Appendix 6.2 Key clinical questions and protocols

Appendix 6.3 ROC curves and forest plots

Appendix 6.4 Search strategiesAppendix 6.5 Health economics evidence and evidence tables

Appendix 6.6 Evidence tables


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Disclaimer

NICE clinical guidelines are recommendations about the treatment and care of

people with specific diseases and conditions in the NHS in England and

Wales.

This guidance represents the view of NICE, which was arrived at after careful

consideration of the evidence available. Healthcare professionals are

expected to take it fully into account when exercising their clinical judgement.

However, the guidance does not override the individual responsibility of

healthcare professionals to make decisions appropriate to the circumstances

of the individual patient, in consultation with the patient and/or guardian or

carer, and informed by the summary of product characteristics of any drugs

they are considering.

Implementation of this guidance is the responsibility of local commissioners

and/or providers. Commissioners and providers are reminded that it is their

responsibility to implement the guidance, in their local context, in light of their

duties to avoid unlawful discrimination and to have regard to promoting

equality of opportunity. Nothing in this guidance should be interpreted in a way

that would be inconsistent with compliance with those duties.


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Foreword

Coeliac disease is believed to be present in up to 1 in 100 of the population

although only about 1015% of people with the condition are clinically

diagnosed. Many of the remainder may be well, but a significant minority will

have chronic problems such as lethargy, gastrointestinal symptoms, or the

effects of anaemia. These result in chronic ill health and often extensive

medical investigation without a definite diagnosis.

Because coeliac disease can be very effectively treated with a gluten-free diet

it is important to identify people with the undiagnosed disease so as to provide

satisfactory individual treatment and also to improve the overall health of the

community.

To improve the recognition of coeliac disease and to increase the number of

people diagnosed with the condition, the Department of Health asked NICE to

produce a short clinical guideline about how the disease should be recognised

and which people should be assessed for the disease.

The Guideline Development Group (GDG) comprised experts in both adult

and paediatric gastroenterology from primary and secondary care, dietitians,

patient members and a clinical immunologist. It was supported by the NICE

Short Clinical Guidelines Technical Team.

The GDG considered systematically identified and reviewed evidence

concerning the recognition of coeliac disease. A new health economic model

was also developed to consider the cost effectiveness of serological tests for

coeliac disease.

The guideline gives recommendations about the clinical signs, symptoms and

types of presentation or conditions that should alert practitioners to consider

the presence of coeliac disease, and suggests a scheme of investigation to

follow when making the diagnosis. It is expected that implementation of the

guideline recommendations will lead to many new cases being diagnosed and

much ill health being alleviated.


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The GDG hopes that this guideline will be sufficiently clear and non-

contentious that its implementation will be routine both in secondary care and

in primary care, where most patients with coeliac disease will present.

Professor Peter D Howdle

Chair, Guideline Development Group


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Patient-centred care

This guideline offers best practice advice on the recognition and assessment

of coeliac disease and the care of children and adults who are undergoing the

diagnostic process for coeliac disease.

This diagnostic process should take into account patients needs and

preferences. People with symptoms and/or signs suggestive of coeliac

disease should have the opportunity to make informed decisions, in

partnership with their healthcare professionals. If patients do not have the

capacity to make decisions, healthcare professionals should follow the

Department of Health (2001) guidelines Reference guide to consent for

examination or treatment (available from www.dh.gov.uk). Healthcare

professionals should also follow a code of practice accompanying the Mental

Capacity Act (summary available from www.publicguardian.gov.uk).

If the patient is under 16, healthcare professionals should follow guidelines in

Seeking consent: working with children (available from www.dh.gov.uk).

Good communication between healthcare professionals and patients is

essential. It should be supported by evidence-based written information

tailored to the patients needs. Diagnosis, treatment and care, and the

information patients are given about it, should be culturally appropriate. It

should also be accessible to people with additional needs such as physical,

sensory or learning disabilities, and to people who do not speak or read

English.

If the patient agrees, families and carers should have the opportunity to be

involved in decisions about diagnosis, treatment and care.

Families and carers should also be given the information and support they

need.

Care of young people in transition between paediatric and adult services

should be planned and managed according to the best practice guidance


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described in Transition: getting it right for young people (available from

www.dh.gov.uk).

Adult and paediatric healthcare teams should work jointly to provide

assessment and services to young people with coeliac disease. Diagnosis

and management should be reviewed throughout the transition process, and

there should be clarity about who is the lead clinician to ensure continuity of

care.


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1 Summary

1.1 Recommendations

When to offer testing

1.1.1 Offer serological testing for coeliac disease to children and adults

with any of the following signs and symptoms:

chronic or intermittent diarrhoea

failure to thrive or faltering growth (in children)

persistent or unexplained gastrointestinal symptoms includingnausea and vomiting

prolonged fatigue (tired all the time)

recurrent abdominal pain, cramping or distension

sudden or unexpected weight loss

unexplained iron-deficiency anaemia, or other unspecified

anaemia.

1.1.2 Offer serological testing for coeliac disease to children and adults

with:

any of the following conditions:

autoimmune thyroid disease

dermatitis herpetiformis

irritable bowel syndrome

type 1 diabetes

or

first-degree relatives (parents, siblings or children) with coeliac

disease.


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1.1.3 Consider offering serological testing for coeliac disease to children

and adults with any of the following:

Addison's disease

amenorrhoea

aphthous stomatitis (mouth ulcers)

autoimmune liver conditions

autoimmune myocarditis

chronic thrombocytopenia purpura

dental enamel defects

depression or bipolar disorder

Downs syndrome

epilepsy

low-trauma fracture

lymphoma

metabolic bone disease (such as rickets or osteomalacia)

microscopic colitis

persistent or unexplained constipation

persistently raised liver enzymes with unknown cause

polyneuropathy

recurrent miscarriage

reduced bone mineral density

sarcoidosis

Sjgren's syndrome

Turner syndrome

unexplained alopecia

unexplained subfertility.

Dietary considerations before testing for coeliac disease

1.1.4 Do not use serological testing for coeliac disease in infants before

gluten has been introduced to the diet.

1.1.5 Inform people (and their parents or carers, as appropriate) that any

testing for coeliac disease is accurate only if the person continues


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to follow a gluten-containing diet during the diagnostic process

(serological tests and biopsy if required).

1.1.6 Inform people that they should not start a gluten-free diet until

diagnosis is confirmed by intestinal biopsy, even if a self-test or

other serological test is positive.

1.1.7 Inform people that when they are following a normal diet

(containing gluten) they should eat some gluten (for example,

bread, chapattis, pasta, biscuits, or cakes) in more than one meal

every day for a minimum of 6 weeks before testing; however, it is

not possible to say exactly how much gluten they should eat.

1.1.8 If a person is reluctant or unable to reintroduce gluten into their diet

before testing:

refer them to a gastrointestinal specialist and

inform them that it may be difficult to confirm a diagnosis of

coeliac disease on intestinal biopsy, and that this may have

implications for the prescribing of gluten-free foods.

Other information before serological testing

1.1.9 Inform people who are considering, or have undertaken, self-testing

for coeliac disease (and their parents or carers) that any result from

self-testing needs to be discussed with a healthcare professional

and confirmed by laboratory-based tests.

1.1.10 Before seeking consent to take blood for serological tests, explain:

what coeliac disease is

that serological tests do not diagnose coeliac disease, but

indicate whether further testing is needed

the implications of a positive test (including referral for intestinal

biopsy and implications for other family members)

the implications of a negative test (that coeliac disease is

unlikely but it could be present or could arise in the future).


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1.1.11 Inform people and their parents or carers that a delayed diagnosis

of coeliac disease, or undiagnosed coeliac disease, can result in:

continuing ill health

long-term complications, including osteoporosis and increased

fracture risk, unfavourable pregnancy outcomes and a modest

increased risk of intestinal malignancy

growth failure, delayed puberty and dental problems (in

children).

Serological tests

1.1.12 All tests should be undertaken in laboratories with clinical pathologyaccreditation (CPA).

1.1.13 Do not use immunoglobulin G (IgG) or immunoglobulin A (IgA)

anti-gliadin antibody (AGA) tests in the diagnosis of coeliac

disease.

1.1.14 Do not use of self-tests and/or point-of-care tests for coeliac

disease as a substitute for laboratory-based testing.

1.1.15 When clinicians request serology, laboratories should:

use IgA tissue transglutaminase (tTGA) as the first choice test

use IgA endomysial antibodies (EMA) testing if the result of the

tTGA test is equivocal

check for IgA deficiency if the serology is negative1

use IgG tTGA and/or IgG EMA serological tests for people withconfirmed IgA deficiency

communicate the results clearly in terms of values, interpretation

and recommended action.

1.1.16 Do not use human leukocyte antigen (HLA) DQ2/DQ8 testing in the

initial diagnosis of coeliac disease. (However, its high negative

1Investigation for IgA deficiency should be done if the laboratory detects a low or very low

optical density on IgA tTGA test or low background on IgA EMA test.


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predictive value may be of use to gastrointestinal specialists in

specific clinical situations.)

After serological testing

1.1.17 Offer referral to a gastrointestinal specialist for intestinal biopsy to

confirm or exclude coeliac disease to people with positive

serological results from any tTGA or EMA test.

1.1.18 If serology tests are negative but coeliac disease is still clinically

suspected, offer referral to a gastrointestinal specialist for further

assessment.


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1.2 Care pathway

Does the person have any of the signs, symptomsor conditions listed in box A or box B?

Yes

No

Is the person on a gluten-containing diet?

Is the person willing/able toreintroduce gluten to theirdiet?

Yes

No

Recognitionanassessmen

t

No

Important: Do not use serological testing for coeliac disease in infants before gluten has been introduced to the diet

Offer serological testing if the person has any of thesigns, symptoms or conditions in box AConsider offering serological testing if the personhas any of the conditions in box B

Person is unlikely to needtesting for coeliac disease atthis point, unless there is acontinuing medical problemor clinical suspicion

Refer them to agastrointestinalspecialist and informthem that it may bedifficult to confirm adiagnosis of coeliacdisease on intestinalbiopsy, and that thismay have implicationsfor their ability to accessprescribed gluten-freefoods


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Dietary considerations before serological testing

Inform people (and their parents or carers as appropriate)that:

testing (serology and biopsy if required) is accurateonly if they follow a gluten-containing diet

when following a gluten-containing diet they should eatsome gluten in more than one meal every day for atleast 6 weeks before testing

they should not start a gluten-free diet until diagnosis isconfirmed by intestinal biopsy (even if a self-test orother serological test is positive)

Other information before serological testing

Inform people who are considering, or who have undertaken, self-testing forcoeliac disease that any result from self-testing needs to be discussed with ahealthcare professional and confirmed by laboratory-based tests.

Before seeking consent to take blood for serological tests, explain:

what coeliac disease is

that serological tests do not diagnose coeliac disease, but indicate whetherfurther testing is needed

the implications of a positive test (including referral for intestinal biopsy andimplications for other family members)

the implications of a negative test (that coeliac disease is unlikely but itcould be present or arise in the future).

Inform people (and their parents or carers as appropriate) that a delayeddiagnosis of coeliac disease, or undiagnosed coeliac disease, can result in:

continuing ill health

long-term complications, including osteoporosis and increased fracture risk,unfavourable pregnancy outcomes and a modest increased risk of intestinalmalignancy

growth failure, delayed puberty and dental problems (in children).

Information

needs


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Serologytestinga

ndafter

Use serological testing for IgA tissuetransglutaminase (tTGA) as a first-choice test

Use IgA endomysial antibodies (EMA) testing ifthe result of the tTGA test is equivocal

Negativeresult

Check for IgAdeficiency

a

Offer IgG tTGA testsand/or IgG EMA tests

Positiveresult

Negative resultbut continuing

clinical suspicion

Positive result

Positive result Negative resultbut continuing

clinical suspicion

Negativeresult, no

furtherreason tosuspectcoeliacdisease

aInvestigation for IgA deficiency should be done if the laboratory

detects a low or very low optical density on IgA tTGA test or lowbackground on IgA EMA test.

Important:

All tests should be undertaken in laboratories with clinical pathology accreditation (CPA) Do not use IgA or IgG anti-gliadin antibody (AGA) tests in the diagnosis of coeliac disease Do not use HLA DQ2/DQ8 testing in the initial diagnosis of coeliac disease (However, its high negative

predictive value may be of use to gastrointestinal specialists in specific clinical situations)

Do not use self-tests and/or point of care tests for coeliac disease as a substitute for laboratory-basedtesting

Unlikely to have coeliacdiseaseNo need to repeat tests

Refer to a gastrointestinalspecialist for intestinal biopsy toconfirm or exclude coeliacdisease


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Signs, symptoms and conditions associated with coeliac disease

Box A. Offer serological testing to children and adults with any of thefollowing signs, symptoms and conditions

Signs and symptoms Conditions

Chronic or intermittent diarrhoea

Failure to thrive or faltering growth (in

children)

Persistent or unexplained gastrointestinal

symptoms including nausea and vomiting

Prolonged fatigue (tired all the time)

Recurrent abdominal pain, cramping or

distension

Sudden or unexpected weight loss

Unexplained iron-deficiency anaemia, or

other unspecified anaemia

Autoimmune thyroid disease

Dermatitis herpetiformis

Irritable bowel syndrome

Type 1 diabetes

First-degree relatives (parents, siblings or

children) with coeliac disease

Box B. Consider offering serological testing to children and adults withany of the following

Addison's disease

amenorrhoea







Downs syndrome

epilepsy

low-trauma fracture

lymphoma

metabolic bone disease (such asrickets or osteomalacia)

microscopic colitis

persistent or unexplainedconstipation

persistently raised liver enzymes withunknown cause

polyneuropathy



sarcoidosis

Sjgren's syndrome

Turner syndrome unexplained alopecia



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Nice clinical guideline 86 Coeliac disease 18

1.3 Overview

1.3.1 Coeliac disease: recognition and assessment

Coeliac disease is a state of heightened immunological response to ingestedgluten in genetically susceptible people. Gluten is a protein that is present in

wheat, barley and rye. Historically, coeliac disease was believed to be

uncommon; however, population-based studies have identified that it is more

common than previously thought.

Coeliac disease has traditionally been associated with mainly gastrointestinal

symptoms (such as diarrhoea, abdominal pain, bloating, constipation and

indigestion), because chronic inflammation of the small intestine is a feature of

the immune response to gluten. However, non-gastrointestinal features of

coeliac disease have been increasingly recognised in people presenting with

the disease. Some people with coeliac disease have no obvious symptoms.

Coeliac disease is considered to be more prevalent in people with

autoimmune conditions such as type 1 diabetes or autoimmune thyroid

disease, and in first-degree relatives of people with coeliac disease.

Coeliac disease can be diagnosed at any age (after the introduction of gluten-

containing foods to the infant weaning diet), and presents in both children and

adults.

Because of the disparate nature of its signs and symptoms, and the historical

belief that it is not a common disease, there is concern that coeliac disease

often goes unrecognised and consequently is underdiagnosed. As a result,

people may present to primary and secondary care on many occasions and

with a range of symptoms before diagnosis. Delayed diagnosis is a concern

because the symptoms of coeliac disease remain untreated and because of

the possible long-term effects of undiagnosed coeliac disease.

There is also some uncertainty about which of the serological tests are most

suitable for use in the diagnostic process for coeliac disease. Small intestinal

biopsy is used as the reference standard for the diagnosis of coeliac disease.


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Although there is ongoing debate about the possibility of diagnosis without the

need for an intestinal biopsy, it is accepted that currently it is needed for a

definitive diagnosis.

This short clinical guideline aims to improve the care of children and adults

with undiagnosed coeliac disease by making evidence-based

recommendations about its recognition, and about using serological testing to

direct referral for definitive diagnosis by intestinal biopsy.

This guideline uses the best available clinical-effectiveness and cost-

effectiveness evidence, which is analysed and discussed by the GDG to

develop recommendations. The GDG considered the signs and symptoms,

conditions likely to coexist with coeliac disease, the role of serological testing

in the diagnostic process up to referral for small intestinal biopsy, and the

information needs of patients and carers throughout this process.

1.3.2 The NICE short clinical guideline programme

Coeliac disease: recognition and assessment' (NICE clinical guideline 86) is a

NICE short clinical guideline. For a full explanation of the NICE guideline

development process, see The guidelines manual (2009) (available from

www.nice.org.uk/guidelinesmanual).

1.3.3 Using this guideline

This document is intended to be relevant to healthcare professionals in

primary and secondary care. The target population is adults and children with

symptoms and/or signs that suggest coeliac disease.

This is the full version of the guideline. It is available from

www.nice.org.uk/CG86. Printed summary versions of this guideline are

available: Understanding NICE guidance (a version for patients and carers)

and a quick reference guide (for healthcare professionals). These are also

available fromwww.nice.org.uk/CG86.
http://www.nice.org.uk/guidelinesmanualhttp://www.nice.org.uk/guidelinesmanualhttp://www.nice.org.uk/CG86http://www.nice.org.uk/CG86http://www.nice.org.uk/CG86http://www.nice.org.uk/CG86http://www.nice.org.uk/CG86http://www.nice.org.uk/CG86http://www.nice.org.uk/CG86http://www.nice.org.uk/guidelinesmanual


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1.3.4 Using recommendations and supporting evidence

For each clinical question the GDG was presented with a summary of the

clinical evidence, and economic evidence if appropriate, derived from the

studies reviewed and appraised. The GDG based the guidelinerecommendations on this information. The link between the evidence and the

view of the GDG in making each recommendation is made explicit in the

'Evidence to recommendations' sections (2.2.3, 2.3.4 and 2.4.5).

2 Evidence review

2.1 Introduction

The clinical-effectiveness and cost-effectiveness evidence that was used in

the development of this guideline is summarised in this section. Further details

about the cost-effectiveness evidence, including details of the economic

model, are given in appendix 6.5; details about the clinical evidence are given

in the tables in appendix 6.6.

The aim of this guideline is to improve the recognition and assessment of

coeliac disease in children and adults; it considers the diagnostic pathway upto referral for intestinal biopsy. Small intestinal biopsy is the reference

standard used throughout this guideline; the studies included are those in

which coeliac disease was confirmed by intestinal biopsy. In 2004 the Agency

for Healthcare Research and Quality (AHRQ) published an evidence

report/technology assessment on coeliac disease. The report included a

series of systematic reviews using clearly defined methods; these reviews

have been included when appropriate to the scope of this guideline. TheAHRQ report, assessed as a well-conducted systematic review, is considered

as high-quality evidence (details of the evidence grading system can be found

in The guidelines manual [2009], available fromwww.nice.org.uk). Other

studies included in this guideline have been mainly cohort-based studies,

notably for the evidence of serological test accuracy. Casecontrol studies

have also been included when appropriate. Both the cohort and casecontrol

studies have limitations resulting from study design, and as such are regarded

as level + evidence. Case series, case reports and studies with small
http://www.nice.org.uk/http://www.nice.org.uk/http://www.nice.org.uk/http://www.nice.org.uk/


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numbers (less than 50 participants) have not been included. When both signs

and symptoms and coexisting conditions have been listed in this guideline

they have been listed alphabetically.

2.2 Prevalence of coeliac disease

2.2.1 Evidence review

The prevalence of coeliac disease has historically been difficult to determine

because in many cases people with coeliac disease do not have specific signs

and symptoms. Difficulties in recognising coeliac disease have resulted in its

prevalence being considerably underestimated.

A search was carried out to identify large population-based studies giving data

on the prevalence of coeliac disease; these are reviewed below.

Overall prevalence of coeliac disease

The AHRQ report (2004) includes studies that considered the prevalence of

coeliac disease in north America and western Europe up to and including

2003. The evidence below includes the AHRQ report with additional relevant

large population-based studies in north America and western Europe from

2003 onwards and studies in other geographical areas from 1990. The AHRQ

report found a prevalence of coeliac disease in children by biopsy of 0.5 to

1.6% (six studies) and by serology of 0.3 to 1.9% (eight studies); in adults the

prevalence by biopsy was 0.07 to1.9% (15 studies) and by serology was 0.2

to 2.7% (22 studies). The three UK-based studies in the AHRQ report are all

of adults, and identify a prevalence of coeliac disease by biopsy of 1.0% and

by serology of 0.8 to 1.9%.

The Avon Longitudinal Study of Parents and Children (a population-based

cohort study) used IgA EMA to investigate children aged 7.5 years and

reported that 1% (54 out of 5470) were serologically positive for coeliac

disease. This study also showed that IgA EMA positive rates were higher in

girls than in boys, odds ratio (OR) 2.12 (95% confidence interval [CI] 1.20 to

3.75) (Bingley et al. 2004).


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Additional international studies in adults used data which was available from

large samples such as people donating blood (Bdioui et al. 2006; Melo et al.

2006; Oliveria et al. 2007; Pereira et al. 2006; Shahbazkha et al. 2003) and

people attending for prenuptial medical checks (Gomez et al. 2001). A further

study used random sampling from a national register (Roka et al. 2007).

These studies found a prevalence of coeliac disease in adults of 0.14 to

0.86%.

Additional international studies in children used data on children younger than

3 years (Castano et al. 2004), samples from an existing public health register

(Korponay-Szabo et al. 1999) and random sampling of school children (Ben

Hariz et al. 2007; Ertekin et al. 2005). These studies identified a prevalence of

coeliac disease in children of 0.64 to 1.17%.

The AHRQ report (2004) also included studies on the prevalence of coeliac

disease in both children and adults in whom coeliac disease was suspected.

These studies were mainly situated in referral centres and the prevalence of

coeliac disease varied widely: in children it was 1.1 to 4.0% with EMA

serology, 4.6 to 17.0% with biopsy; in adults it was 1.5% with EMA serology,

11.6 to 50.0% with biopsy.

Prevalence in first-degree relatives

The AHRQ report (2004) included studies that considered the prevalence of

coeliac disease in first-degree relatives of people who had had a diagnosis of

coeliac disease. These studies showed a prevalence of 2.8 to 17.2% with

serology (five studies) and 5.6 to 44.1% with biopsy (12 studies). The three

studies completed in the UK all reported a prevalence found using biopsy, andreported a prevalence in first-degree relatives of 5.6 to 22.5%.

Three additional studies were included (Fraser et al. 2006; Biagi et al. 2008;

Szaflaraka-Sczepanik et al. 2001). These reported a prevalence of coeliac

disease in first-degree relatives of 2 to 17.7%. The study by Fraser et al. was

in the UK and reported a prevalence of 5.5%.


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2.2.2 Evidence statements

In national studies in the UK, the prevalence of coeliac disease ranges

between 0.8% and 1.9%. This is broadly similar to other international studies.

Among first-degree relatives of people with coeliac disease, the majority of

studies report a prevalence of coeliac disease between 4.5% and 12%.

There is limited evidence that the prevalence of coeliac disease is twice as

high in females as in males.

2.3 The possible long-term consequences of

undiagnosed coeliac disease

2.3.1 Evidence review

The review considered only the possible long-term consequences of

undiagnosed coeliac disease, and therefore did not include any studies that

considered people with diagnosed coeliac disease. It did not include

consideration of any long-term consequences of coeliac disease that may

affect coexisting conditions such as type 1 diabetes. The included studies

looked at undiagnosed coeliac disease or where other possible long-term

consequences had been noted as present at the point of diagnosis. It should

be noted that these possible long-term consequences are associations and

the studies are not considered to provide evidence of a causal relationship. In

all but one of the included studies coeliac disease had been confirmed by

biopsy; the other study included pregnant women and intestinal biopsy was

not considered ethical in those near to delivery (Greco et al. 2004). Overall

evidence was identified in three areas: pregnancy outcomes, fracture risk and

malignancy.

Pregnancy outcomes

An Italian study of 5055 women admitted to obstetric and gynaecological

wards (Greco et al. 2004) identified no pregnancy outcomes for which there

was a significant difference between women with and without coeliac disease.

Outcomes included risk of spontaneous abortion, premature delivery, low birth

weight and intrauterine growth retardation (IUGR).


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A Swedish study analysed data on people from a national inpatient register

who had a hospital-based discharge record of coeliac disease (Ludvigsson et

al. 2005). It included 929 women whose coeliac disease had not been

diagnosed when they gave birth, and 2,822,805 women without coeliac

disease. There were significant differences between outcomes in the two

groups of women. IUGR was reported in 5.5% of mothers with undiagnosed

coeliac disease, and in 3.1% of mothers without coeliac disease (adjusted

odds ratio [OR] 1.62, 95% confidence interval [CI] 1.22 to 2.15, p = 0.001).

The equivalent figures for low-birth-weight were 7.0% and 3.4% (adjusted OR

2.13, 95% CI 1.66 to 2.75, p < 0.001); for very-low-birth-weight 1.2% and

0.5% (adjusted OR 2.45, 95% CI 1.35 to 4.43, p = 0.003); for preterm birth

8.0% and 5.0% (adjusted OR 1.71, 95% CI 1.35 to 2.17, p < 0.001); and for

caesarean section 3.4% and 2.3% (adjusted OR 1.82, 95% CI 1.27 to 2.60,

p = 0.001). No significant difference was found between the groups for very

preterm birth (before 30 weeks) or for babies with low Apgar scores (less

than 7).

Fracture risk

A second Swedish study using the national inpatient register (Ludvigsson etal. 2007) considered hip fractures (14,187 in patients with coeliac disease;

68,852 in patients without coeliac disease) and any fractures (13,724 in

patients with coeliac disease; 65,627 in patients without coeliac disease). The

estimated association of coeliac disease and prior fractures showed an

increased risk of diagnosis with coeliac disease after hip fracture (OR 2.0,

95% CI 1.6 to 2.5, p < 0.001) and after any fracture (OR 1.6, 95% CI 1.5 to

1.8, p < 0.001). This study also identified significantly higher rates of hip

fractures in people with undiagnosed coeliac disease compared with those

with diagnosed coeliac disease. This increased risk was seen throughout the

time period from 10 years to 0.01 years before diagnosis of coeliac disease.

A Danish study used the national patient discharge register to consider

fracture risk in people with coeliac disease (Vestergaard et al. 2002). This

study identified no increase in fracture risk before diagnosis of coeliac disease

compared with matched controls for skull and jaw fractures, spine, rib and


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pelvis fractures, upper arm fractures, forearm fractures, Colles fractures,

hand and finger fractures, hip and femur fractures, fractured neck of femur,

lower leg fractures, foot fractures and osteoporosis.

Malignancy

A US study considered the standardised mortality ratio (SMR) of observed to

expected rates for cancers that were diagnosed before or simultaneously with

coeliac disease diagnosis (Green et al. 2003). Although numbers were small,

this study identified significant SMRs for non-Hodgkins lymphoma (4

observed cases compared with 0.7 expected, SMR 5.3, 95% CI 2.3 to 13,

p < 0.001), small bowel cancer (3 vs. 0.1, SMR 45, 95% CI 34 to 61,

p < 0.001), oesophageal cancer (3 vs. 0.2, SMR 16, 95% CI 9.7 to 26,

p < 0.001) and melanoma (4 vs. 0.8, SMR 5, 95% CI 2.1 to 12, p < 0.001). It

did not identify a significant difference SMR for colon cancer, breast cancer

and total cancers.

An Italian study considered the impact of delayed diagnosis of coeliac disease

on cancer risk using a standardised incidence ratio (SIR) of observed

compared with expected cases in 1968 adults with diagnosed coeliac disease

(Silano et al. 2007). In this study 55 people were diagnosed with cancer

before or simultaneously with coeliac disease diagnosis, compared with

42.1 expected cases (SIR 1.3, 95% CI 1.0 to 1.7). Although numbers involved

were small, this study identified 20 observed cases compared with

4.2 expected of non-Hodgkin's lymphoma (SIR 4.7, 95% CI 2.9 to 7.3), for

colon cancer 7 compared with 6.2 (SIR 1.1, 95%CI 0.68 to 1.56), for small

bowel cancer 5 compared with 0.19 (SIR 25, 95% CI 8.5 to 51.4) and for

Hodgkins lymphoma 4 compared with 0.4 (SIR 10, 95% CI 2.7 to 25). A lower

risk was identified for breast cancer in people with newly diagnosed coeliac

disease (3 vs. 14, SIR 0.2, 95% CI 0.04 to 0.62).


There is evidence that undiagnosed maternal coeliac disease has a negative

effect on intrauterine growth and birth weight, and is associated with

increased preterm birth and caesarean section rates.


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Evidence suggests an association between undiagnosed coeliac disease and

an increased risk of fractures.

Undiagnosed coeliac disease is associated with an increased risk of non-

Hodgkins and Hodgkins lymphoma and small bowel cancer, but overall rates

are low.

2.3.3 Linking evidence to recommendations

The GDG discussed the evidence, agreed the evidence statements relating to

the possible effects of long-term undiagnosed coeliac disease, and developed

recommendations. This discussion is summarised here:

The GDG agreed the need to include information about the risk of long-

term complications of undiagnosed coeliac disease. It noted that although

there is an increased risk of the specific cancers with undiagnosed coeliac

disease, the overall risk of developing these cancers is low.

The GDG discussed the different possible long-term effects in children and

adults and agreed an additional recommendation for children specifying

growth failure, delayed puberty and dental complications.

2.4 Signs and symptoms of coeliac disease and

coexisting conditions with coeliac disease

2.4.1 Evidence review signs and symptoms

Recognition and assessment of coeliac disease can be difficult because of the

variety of presenting signs and symptoms.

The AHRQ report considered the prevalence of coeliac disease in adults with

iron-deficiency anaemia and in adults with low bone-mineral density. Eight

studies from the AHRQ report with 50 or more participants were included;

these were all in adults with biopsy-proven coeliac disease. The prevalence of

coeliac disease in people with iron-deficiency anaemia ranged from 2.3 to

15%. Four studies from the AHRQ report considered people with low bone

mineral density; these studies identified a prevalence of coeliac disease

ranging from 0 to 3%.


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Further papers included in this review considered people with coeliac disease

at the point of it being diagnosed and the features that they presented with.

(Those reported in table 1 are where 5% or more of participants had the

presenting feature.)

Table 1 Presenting features of people with coeliac disease

Feature People withthe feature

Adults/children Studies

Iron-deficiencyanaemia

39.3%

25%

11.7%

adults and children

adults

adults and children

Bottaro 1999

Brandimarte 2002

Emami 2008

Other or unspecifiedanaemia

16%

3 to19%

3.0 to 12.7%

23.3%

adults and children

children

adults

older adults

Dickey 1997

Garampazzi 2007

Rampertab 2006

Vilppula 2008

Anorexia 7.8 %

25.6 to 35.1%

adults and children

children

Bottaro 1999

Bottaro 1993

Weight loss 43.6 to 59.6%

6%

15.6%

16.7%

children

adults and children

adults

older adults

Bottaro 1993

Dickey 1997

Hopper 2008

Vilppula 2008

Abdominal

distension/bloating

28.4 to 35.8%

10%20 to 39%

children

adults and childrenchildren

Bottaro 1993

Emami 2008Garampazzi 2007

Abdominal pain 12%

8.2%

11 to 21%

adults and children

adults and children

children

Dickey 1997

Emami 2008

Garampazzi 2007

Abdominalpain/distension/flatulence

31.7% older adults Vilppula 2008

Vomiting 26.1 to 32.5% children Bottaro 1993

Flatulence 5.4% adults and children Emami 2008

Diarrhoea 70.2 to 75.2%

51%

13.1%

12 to 60%

42.9%

37.2 to 91.3%

25%

children

adults and children

adults and children

children

adults

adults

older adults

Bottaro 1993

Dickey 1997

Emami 2008

Garampazzi 2007

Hopper 2008

Rampertab 2006

Vippula 2008

Short stature/growthfailure

19.2%

20.2 to 30.8%

adults and children

children

Bottaro 1999

Bottaro 1993

Irritability 10.3 to 13.9% children Bottaro 1993Alopecia 10% adults Brandimarte 2002


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Feature People withthe feature

Adults/children Studies

Osteoporosis 6% adults Brandimarte 2002

Recurrent aphthousstomatitis

6% adults Brandimarte 2002

Amenorrhoea/recurrent abortion


Hypertransaminase-aemia


Abnormal liverbiochemistry

5% adults and children Dickey 1997

Chronic fatigue 7%

8.3%

adults and children

older adults

Dickey 1997

Vilppula 2008

Failure to thrive 48 to 89% children Garampazzi 2007

Constipation 4 to 12% children Garampazzi 2007

Irregular bowel habits 4 to 12% children Garampazzi 2007

Three further studies considered a specific symptom or presentation and the

percentage of those presenting with it who also had coeliac disease:

Karnam et al. (2004) considered adults who were undergoing endoscopy

for iron-deficiency anaemia and found 3 of 105 people (2.9%) had coeliac

disease.

Imanzadeh et al. (2005) considered children with small bowel type chronic

diarrhoea and found that 54 of 825 people (8.96%) had coeliac disease.

Sanders et al. (2005) considered adults with acute abdominal pain and

found that 9 of 300 people (3%) had coeliac disease. In people with non-

specific abdominal pain 10.5% had coeliac disease.

Some people presenting with the features of coeliac disease in the studiessummarised in table 1 had a coexisting condition at the point of diagnosis of

coeliac disease:

dermatitis herpetiformis 10%, Brandimarte 2002 (adults); 1%, Dickey

1997 (adults and children)

irritable bowel syndrome 20.2%, Emami 2008 (adults and children)

liver disorder 0.85%, Emami 2008 (adults and children)

rheumatological disorder 0.28%, Emami 2008 (adults and children)


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Crohns disease 0.57%, Emami 2008 (adults and children)

bone disease 0 to15%, Rampertab 2006 (adults)

malignancy 5 to 21.7%, Rampertab 2006 (adults).

2.4.2 Evidence review coexisting conditions

The studies included for this review considered coexisting conditions

associated with coeliac disease up to and including the point of it being

diagnosed. Studies that considered subsequent development of conditions in

people who had been diagnosed with coeliac disease were excluded. The

relationship between the coexisting conditions and coeliac disease here is not

considered to be causal; the aim was to examine whether people with certain

conditions have a higher rate of coeliac disease than the general population.

Papers in which there was a substantial discrepancy between numbers of

people who had serological tests and numbers of people who had biopsies

were excluded, because of the possibility that results could be biased if not all

those with positive serology had a biopsy.

Type 1 diabetes

The AHRQ report included papers on the prevalence of coeliac disease inpeople with type 1 diabetes; 21 of these studies (people with coeliac disease

proven by biopsy; each had 50 or more participants) were included here.

These studies identified a prevalence of coeliac disease in people with type 1

diabetes of 1.4 to 8.2% in children, 0.3 to 11.3% in adults and 1.7 to 5.7% in

combined child and adult studies. Two additional papers also considered

people with type 1 diabetes: one in children reported that 6.6% had coeliac

disease (Salardi et al. 2008) and one in adults reported that 6.4% had coeliac

disease (Picarelli et al. 2005).

Other conditions

Papers were included that considered cohorts of people with specified other

conditions who were tested for coeliac disease (see table 2).


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Table 2 Coexisting conditions and coeliac disease

Condition Study participants Participants withcoeliac disease

Study authorand year

Arthritis 160 adults with rheumatoidarthritis

0.63% Francis 2002

62 children with juvenilechronic arthritis

1.5% George 1996

119 children with juvenilechronic arthritis

2.5% Lepore 1996

Autoimmunethyroid

136 adults withautoimmune thyroiditis

2.9% Guliter 2007

152 adults withautoimmune thyroiddisease

3.29% Sategna-Guidetti 1998

Down

syndrome

1453 children and adults 4 (0.3%), adjusted risk

ratio 4.7 (95% CI 1.3to 12.2)

Goldacre 2004

1110 children, 92 adults 55 (4.6%) Bonamico 2001

Epilepsy 255 children and adults 2 (0.8%) Pratesi 2003

177 adults 1:44 (2.3%) Cronin 1998

Inflammatoryboweldisease

354 adults (173 Crohnsdisease, 154 ulcerativecolitis, 27 other conditions)

0.85% Leeds 2007

Irritable bowelsyndrome

300 adults OR 7 (95% CI 1.7 to28.0)

Sanders 2001

Liver disease 624 adults with chronichepatitis C

0% Thevenot 2007

738 children and adultswith chronic liver disease

1:185 (0.45%) Germenis 2005

57 adults with primarybiliary cirrhosis

7% Dickey 1997

Lymphoidmalignancy

298 adults 0.67% Farre 2004

Myocarditis 187 adults withautoimmune myocarditis

4.4% (p < 0.003 vs.control group)

Frustaci 2002

Sjgren'ssyndrome

111 adults 4.54% Szodoray 2004

Subfertility 99 women 3.03%(p = 0.037unexplained infertilityvs. control group)

Meloni 1999

150 women 2.7% all unexplainedinfertility (p = 0.06 vs.control group)

Collin 1996

Turnersyndrome

389 children and adults 25 (6.4%) Bonamico 2002


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One study was also included that identified the existing conditions of people at

the point of diagnosis of coeliac disease (Collin et al. 1994). Also included

were studies in which logistical regression had been used to investigate

coeliac disease that developed following a prior history of a coexisting

condition (see table 3).

Table 3 Coexisting conditions and coeliac disease

Study group:peoplewith newlydiagnosed coeliacdisease

Coexisting conditions

335 adults (335control group)

(figures are givenfor study groupfirst, control groupsecond)

(Collin 1994)

Endocrine disorders: 12% (study group) vs. 4.2% (control group),p = 0.0003

insulin dependent diabetes 18 (5.4%) vs. 5 (1.5%),p = 0.0094

autoimmune thyroid 18 (5.4%) vs. 9 (2.7%)

Connective tissue disorder: 7.2% vs. 2.7%, p = 0.011

Sjgren's syndrome 11 (3.3%) vs. 1 (0.3%), p = 0.0059

rheumatoid arthritis 6 (1.8%) vs. 7 (2.1%)

Pulmonary disorders:

asthma 9 vs. 12

sarcoidosis 5 vs. 0

Neurological disorders: epileptic seizures 5 vs. 3

dementia 5 vs. 1

Liver diseases: 4 vs. 0

14,349 adults andchildren (69,998control)(Ludvigsson 2007a)

Increased risk of coeliac disease in those with prior sarcoidosisOR 3.58, 95% CI 1.98 to 6.45, p < 0.001

14,371 adults andchildren (70,096control)

(Ludvigsson 2007b)

Increased risk of coeliac disease in those with priorpolyneuropathy OR 5.4, 95% CI 3.6 to 8.2, p < 0.001

Other neurological diseases were not associated withsubsequent coeliac disease

13,776 adults andchildren (66,815control)(Ludvigsson 2007c)

Increased risk of coeliac disease in those with history of mooddisorder:

prior depression OR 2.3, 95% CI 2.0 to 2.8, p < 0.001

prior bipolar disorder OR 1.7, 95% CI 1.2 to 2.3, p = 0.001


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Study group:peoplewith newlydiagnosed coeliacdisease

Coexisting conditions

13,818 adults and

children (66,584control)(Ludvigsson 2007d)

Increased risk of coeliac disease in those with history of liver

disorder: acute hepatitis OR 4.98, 95% CI 1.59 to 12.06, p = 0.004

chronic hepatitis OR 5.79, 95% CI 3.13 to 10.70,p < 0.001

primary sclerosing cholangitis OR 4.42, 95% CI 2.38 to8.24, p < 0.001

fatty liver OR 5.83, 95% CI 1.96 to 17.36, p < 0.002

ascites OR 5.00, 95% CI 2.08 to 12.01, p < 0.001

liver failure, extended OR 5.88, 95% CI 4.05 to 8.54,p < 0.001

liver failure, restricted OR 8.33, 95% CI 1.99 to 34.87,p < 0.004

liver cirrhosis/fibrosis OR 5.83, 95% CI 3.86 to 8.81,p < 0.001

primary biliary cirrhosis OR 15.00, 95 %CI 4.84 to 46.51,p < 0.001

hepatomegaly OR 2.00 (95% CI 0.39 to 10.31) notsignificant

14,335 children andadults (69,888

control)(Ludvigsson 2007e)

Increased risk of coeliac disease in those with prior tuberculosis:

OR 2.5, 95% CI 1.75 to 3.55, p < 0.001

15,533 children andadults (14,491inpatient referencecontrols)(Ludvigsson 2008)

Increased risk of coeliac disease in those with prior sepsis

OR 2.2, 95% CI 1.7 to 3.0, p < 0.001

14,366 children andadults (70,095control)

(Elfstrm 2007)

Increased risk of coeliac disease in those with prior Addison'sdisease OR 8.6, 95% CI 3.4 to 21.8

14,347 adults andchildren (69,967control) (Olen2008)

Increased risk of coeliac disease in those with history ofthrombocytopenia purpura OR 2.96, 95% CI 1.60 to 5.50, p= 0.001; and those with prior chronic thrombocytopenia purpuraOR 6.00, 95% CI 1.83 to 19.66, p = 0.003


In children and adults, coeliac disease can present with a broad range of

signs and symptoms. The most frequent are:

abdominal pain, cramping or distension



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failure to thrive or faltering growth in children

fatigue

iron-deficiency anaemia

nausea or vomiting weight loss.

The following findings may also be present when coeliac disease is

diagnosed:

abnormal liver biochemistry

alopecia

amenorrhoea


constipation


epilepsy

microscopic colitis

osteoporosis

recurrent abortion

type 1 diabetes.

There is good evidence that coeliac disease has an increased prevalence in

people with:

autoimmune thyroid disease (up to 7%)

irritable bowel syndrome (up to 7%)

type 1 diabetes (210%).

There is some evidence that coeliac disease has an increased prevalence in

people with:


chronic thrombocytopenic purpura

depression/bipolar disorder

Downs syndrome


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epilepsy

liver conditions

lymphoid malignancy

polyneuropathy Sjgren's syndrome

sarcoidosis

Turner syndrome


2.4.4 Linking evidence to recommendations

The GDG discussed the evidence and agreed the evidence statements

relating to the signs and symptoms of coeliac disease and the coexisting

conditions, and developed recommendations. This discussion is summarised

here:

The GDG agreed that there were certain signs and symptoms and

coexisting conditions (as well as the known risk factor of being a first-

degree relative of a person with coeliac disease) that are sufficiently

associated with coeliac disease that people with them should be offered

serological testing, and developed recommendations to reflect this. The

GDG discussed the historic division of symptoms into gastrointestinal and

non-gastrointestinal and concluded that it would be more beneficial to

identify the overall signs and symptoms for which testing would be

recommended. The GDG further discussed the non-specific nature of many

of the signs and symptoms and consequently added 'unexplained' and

'chronic' to the description of some signs and symptoms to ensure thatpeople who may have coeliac disease are identified.

The GDG agreed a list of further signs, symptoms and coexisting

conditions for which they wanted to raise awareness of the link with coeliac

disease. Therefore recommendations were developed that identified where

offering serological testing for coeliac disease should be considered.

The GDG discussed weight loss as a feature of coeliac disease and noted

that, although weight loss can be a symptom of coeliac disease, thetraditional view of a patient with coeliac disease being underweight is no


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longer true and that patients may present underweight, at a normal weight

or overweight.

Recommendation 1.1.1

Offer serological testing for coeliac disease to children and adults with any of

the following signs and symptoms:


failure to thrive or faltering growth (in children)

persistent or unexplained gastrointestinal symptoms including nausea and

vomiting

prolonged fatigue (tired all the time) recurrent abdominal pain, cramping or distension

sudden or unexpected weight loss

unexplained iron-deficiency anaemia, or other unspecified anaemia.


Offer serological testing for coeliac disease to children and adults with:

any of the following conditions: autoimmune thyroid disease


irritable bowel syndrome

type 1 diabetes

or

first-degree relatives (parents, siblings or children) with coeliac disease.


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Consider offering serological testing for coeliac disease to children and adults

with any of the following:

Addison's disease

amenorrhoea







Downs syndrome

epilepsy

low-trauma fracture

lymphoma

metabolic bone disease (such as rickets or osteomalacia)

microscopic colitis

persistent or unexplained constipation

persistently raised liver enzymes with unknown cause

polyneuropathy



sarcoidosis

Sjgren's syndrome

Turner syndrome

unexplained alopecia



Do not use serological testing for coeliac disease in infants before gluten has

been introduced to the diet.


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2.5 Serological tests in the diagnostic process for coeliac

disease

2.5.1 Evidence review information for patients before testing

The search strategy was designed to identify any studies that relate

specifically to the information needs and support of patients and parents or

carers before the diagnosis of coeliac disease. No studies were identified.

2.5.2 Evidence review serological tests

This review incorporated studies that included a blood sample drawn from

children or adults suspected of having coeliac disease. This suspicion may

have been based on clinical symptoms, an existing condition (such as type 1

diabetes) or having a first-degree relative with coeliac disease. The included

studies were mainly cohort studies, which provided the best quality evidence.

The data were synthesised and are presented in the form of forest plots and

receiver operating characteristic (ROC) curves (see appendix 6.3). Summary

statistics have not been included because the studies were not considered

homogenous, the methodology for the meta-analysis of diagnostic studies is

not clear and expert opinion in this area varies. Within the studies different kits

and different cut-off values were used for the analysis2

IgA AGA

. Further differences

between studies were different or incompletely reported biopsy strategies,

possible variability between laboratories or operators, the use of different

samples or studies taking place in several different countries.

The serological tests considered for this review were:

IgG AGA

IgA EMA

IgG EMA

IgA tTGA

IgG tTGA.

2If studies used different cut-off levels, the data used were that of the manufacturers

recommended cut-off levels.


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Table 4 summarises the studies, total participants, test methods (enzyme-

linked immunosorbent assay [ELISA] or diffusion in gel [DIG]) and substrate

used for EMA (human umbilical cord [HU] or monkey oesophagus [ME]) and

for tTGA (human recombinant [HR] or guinea pig [GP]) in the included studies.

Table 4 Summary of serological test studies

Serologicaltest

Number ofstudiesincludingthis test

Totalparticipants

Methods

IgA AGA 31 5600 24 used ELISA, 5 used DIG-ELISA, 1used immunohistochemistry, 1 usedimmunofluorescence

IgG AGA 25 4820 20 used ELISA, 3 used DIG-ELISA, 1used immunohistochemistry, 1 usedimmunofluorescence

IgA EMA ME 21 5265 18 used immunofluorescence, 2 usedELISA, 1 used DIG-ELISA, 1 unknown

IgA EMA HU 3 264 3 used immunofluorescence

IgG EMA ME 1 89 1 used immunofluorescence

IgA tTGA GP 8 946 8 used ELISA

IgA tTGA HR 11 3853 9 used ELISA, 1 used radiobindingassay, 1 unknown

IgG tTGA GP 1 111 1 used ELISA

IgG tTGA HR 1 254 1 unknown

IgA deficiency

People with IgA deficiency will have a false negative result if IgA-based

serological tests are used in the diagnosis of coeliac disease. It has been

suggested that there has been inadequate evaluation of IgA deficiency while

testing for coeliac disease, which has resulted in the underdiagnosis of both

(McGowan et al. 2008). Therefore, this guideline also considered the use of

IgA-deficiency testing and IgG-based serological testing in the diagnostic

process for coeliac disease.

Included studies

All studies considered people with suspected coeliac disease who had one of

the included serological tests and had coeliac disease confirmed by biopsy.

There were 29 studies included from the AHRQ (2004) report, 18 in children


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(Altuntas et al. 1998; Artan et al. 1998; Ascher et al. 1996; Bahia et al. 2001;

Bode et al. 1993; Chan et al. 2001; Chartrand et al. 1997; Chirdo et al. 1999;

Iltanen et al. 1999; Kumar et al. 1989; Lindberg et al. 1985; Lindquist et al.

1994; Maki et al. 1991; Meini et al. 1996; Poddar et al. 2002; Rich et al. 1990;

Russo et al. 1999; Wolters et al. 2002), seven in adults (Bardela et al. 2001;

Bode et al. 1994; Carroccio et al. 2002; Kaukinen et al. 2000; McMillan et al.

1991; Valdimarss et al. 1996; Vogelsang et al. 1995) and four in children and

adults (Carroccio et al. 2002; Gonczi et al. 1991; Tesei et al. 2003; Troncone

et al. 1999). A further 14 studies were identified from the search, four in

children (Del Rosario et al. 1998; Liu et al. 2003 and 2005; Viola et al. 2004),

six in adults (Abrams et al. 2006; Hopper et al. 2008; Johnston et al. 2003;

Kocna et al. 2002; Niveloni et al. 2007; Reeves et al. 2006) and four in

children and adults (Carroccio et al. 2006; Dickey et al. 1997; Emami et al.

2008; Rostami et al. 1999). The largest of the additional studies was based in

the UK and included a cohort of 2000 adults, 77 of whom were diagnosed with

coeliac disease, and included data on IgA/IgG AGA, IgA tTGA and IgA EMA

with biopsy (Hopper et al. 2008).


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Table 5 Sensitivity/specificity of serological tests for coeliac disease

Serologicaltest

Studies Sensitivity Specificity

IgA AGA 31 studies (5600participants)

18 child studies

10 adult studies

3 child/adult studies

Range 23 to100%

(adults 46 to 100%)(children 23 to100%)

Range 45 to100%

(adults 45 to 100%)(children 51 to 99%)

IgG AGA 25 studies (4830participants)

15 child studies

8 adult studies


Range 46 to 100%

(adults 22 to 100%)

(children 71 to100%)

Range 77 to 99%

(adults 41 to 97%)

(children 38 to 99%)

IgA EMA 23 studies (5529

participants)10 child studies

9 adult studies


Range 68 to 100%

(adults 68 to 100%)(children 46 to100%)

Range 89 to 100%

(adults 94 to 100%)(children 77 to 100%)

IgG EMA 1 adult study (89participants)

Sensitivity 39% Specificity 98%

IgA tTGA 19 studies (4799participants)

6 child studies

9 adult studies


Range 38 to 100%

(adults 71 to 100%)

(children 89 to100%)

Range 25 to 100%

(adults 65 to 100%)

(children 25 to 100%)

IgG tTGA 2 studies (365participants)

1 adult study

1 child/adult study

Sensitivity 23 to85%

Specificity 89 to 98%

The overall efficacy of the IgA AGA, IgA EMA and IgA tTGA serological tests

was summarised in forest plots and ROC curves (see appendix 6.3). The

ROC curves below show the overall results for the IgA AGA, tTGA and EMA

tests. They show a lower level of accuracy for the IgA AGA than the other

tests, with both IgA EMA and IgA tTGA identified as having high levels of both

sensitivity and specificity. For AGA the IgA serological tests results appeared

to show higher sensitivity and specificity than the IgG tests. For IgG tTGA and

IgG EMA there were insufficient data available to draw reasonable

conclusions.


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L eg endIg A AGAIg A EMAIg A tTG

00 .10 .20 .30.40.50.60.70.80 .910

0 .1

0 .2

0 .3

0 .4

0 .5

0 .6

0 .7

0 .8

0 .9

1

S pe cific ity

Se nsit ivit y

Figure 1 IgA overall results for anti-gliadin antibodies, anti-endomysialantibodies and anti tissue transglutaminase antibodies

Combined and sequence testsA small number of papers considered the sensitivity and specificity of test

combinations or sequencing of tests. One large UK study in adults (Hopper et

al. 2008) considered the use of IgA tTGA and EMA. This study identified

improvements in positive predictive value (PPV) and some small differences

in sensitivity, specificity and negative predictive value (NPV) if both tests were

used, either in a two-step process or simultaneously, compared with if tests

were completed individually.

A second UK-based paper (Johnston et al. 2003), also in adults, considered

the results if either IgA tTGA or EMA were positive. Positive results for either

test gave a lower PPV than was found with each test individually, and a higher

NPV than IgA tTGA.

A paper from the Czech Republic (Kocna et al. 2002) considered a two-step

screening algorithm and identified IgA/IgG AGA to be the least accurate


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first-step marker if it is followed by biopsy, with IgA EMA the most accurate

first-step marker if it is followed by IgA tTGA.

Three studies in the AHRQ report considered the use of IgA/IgG AGA

together or each individually; they did not find the combination results to be

notably different from the individual tests.

Human leukocyte antigen tests

Coeliac disease has a genetic association with certain types of type II human

leukocyte antigens (HLA); HLA DQ2 is found in 95% of people with coeliac

disease and HLA DQ8 in most of the remaining 5%. No studies identified by

the searches considered the sensitivity and specificity of the HLA DQ2 and

DQ8 tests in coeliac disease. The AHRQ report identified papers that

considered the prevalence of HLA DQ2 and DQ8 in a population of people

with coeliac disease, but these studies were not designed to determine the

diagnostic utility of HLA DQ2 or DQ8. Three studies in the AHRQ report were

completed in people with biopsy-proven coeliac disease; these had sensitivity

results of 87 to 90% and specificity of 70 to 81%.

AgeROC curve analysis categorising studies into those with child participants,

those with adult participants and those with mixed (child and adult)

participants reflected the overall analysis, with both IgA EMA and IgA tTGA

(there is insufficient evidence for IgG in either test to plot on the curves)

showing considerably higher levels of sensitivity and specificity than IgA or

IgG AGA.

One study (Viola 2004) also considered IgA AGA, IgA EMA and IgA tTGA

results in children 2 years and younger and those older than 2 years. It found

similar results in both age categories for IgA tTGA and for IgA EMA.


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Subgroups

The search for this question was designed to identify studies in which there

was evidence that the serological tests for coeliac disease performed in any

way differently from the general population. The only areas in which studies

were identified were liver disease and IgA deficiency.

Liver disease: one study of 105 participants who had primary biliary

cirrhosis reported a specificity range for IgA tTGA of 82.5 to 97.1% and

95.1 to 100% for IgG tTGA (Bizzaro et al. 2006). The authors noted that

with almost all the antibody concentrations IgA tTGA was close to the cut-

off level, and that positive results were inconsistent between the test kits.

They identified a concern about the false-positive rate with IgA tTGA testing

in people with primary biliary cirrhosis, although only six participants had

biopsies.

IgA deficiency: one paper was identified that considered the use of IgG

AGA and IgG tTGA tests in 126 children with IgA deficiency (Lenhardt et al.

2004). Eleven were diagnosed with coeliac disease: all were IgG tTGA

positive and five were also IgG AGA positive, this suggests that IgG tTGA

is more accurate than IgG AGA in children with IgA deficiency.

Newer tests

Deamidated gliadin

Two papers were included that considered the use of deamidated gliadin

peptide (DGP)-based assays as a diagnostic tool for coeliac disease. The first

paper considered the use of IgA and IgG antibodies to synthetic DGP and

tTGA in 176 children (Agardh et al. 2007) and found 119 (68%) with coeliac

disease.


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Table 6 Sensitivity and specificity results for deamidated gliadin (Agardhet al. 2007)

Antibody Sensitivity Specificity PPV NPV

IgA/G DGP/tTGA 100% 94.7% 97.5% 100%

IgA/G DGP 97.5% 98.2% 99.1% 94.9%IgA DGP 90.8% 94.7% 97.3% 83.1%

IgG DGP 95.0% 98.2% 99.1% 90.3%

IgA tTGA 96.6% 100% 100% 93.4%

IgG tTGA 12.6% 100% 100% 35.4%

The second study considered 141 adults and used IgA tTGA and IgA/IgG

DGP; 60 were diagnosed with coeliac disease (Niveloni et al. 2007).

Table 7 Sensitivity and specificity results for deamidated gliadin(Niveloni et al. 2007)

Antibody Sensitivity Specificity PPV NPV

IgA DGP 98.3% 93.8% 92.2% 98.7%

IgG DGP 96.7% 100% 100% 97.6%

IgA + IgG DGP 98.3% 98.8% 98.3% 79.6%

IgA tTGA 95.0% 97.5% 96.6% 96.3%

IgA DGP + tTGA 100% 97.5% 96.7% 100%

IgG DPG + IgA tTGA 100% 97.5% 96.7% 100%

IgA+IgG DGP + tTGA 100% 96.3% 95.2% 100%

Results for both of these studies using deamidated gliadin peptide showed

sensitivity and specificity values similar to those found with tTGA.


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Immunochromatographic sticks

One paper was included that considered the use of immunochromatographic

sticks3

IgA/G tTGA (tTG stick): children sensitivity 97%, specificity 98%; adults

sensitivity 83%, specificity 100%

for tissue transglutaminase and antigliadin antibody screening in 286

children and 49 adults (Ferre-Lopez et al. 2004); 142 (51%) children and 30

(61%) adults were diagnosed with coeliac disease. Sensitivity and specificity

results for immunochromatographic sticks were broadly similar to those from

the ELISA method:

IgA tTGA (tTG-AGA stick): children sensitivity 96%, specificity 98%; adults


IgA AGA (tTG-AGA stick): children sensitivity 89%, specificity 96%; adults


IgA tTGA + AGA (stick, one test): children sensitivity 99%, specificity 95%;

adults sensitivity 86%, specificity 100%.


The IgA tTGA and IgA EMA serological tests show high levels of sensitivityand specificity in the diagnostic process for coeliac disease.

Gliadin antibody serological tests show lower levels of sensitivity and

specificity than tTGA and EMA.

Based on limited clinical evidence, combination testing with IgA tTGA and IgA

EMA does not appear to substantially to improve accuracy in the diagnostic

process.

There is limited evidence that IgA tTGA yields more false positive results in

people with liver disease than in the general population.

Serological tests have comparable accuracy in children and in adults.

Newer tests for deamidated gliadin may be useful but require further

evaluation.

3Can be used for self-test or point of care testing.


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Limited evidence suggests that point-of-care tests and self tests may be

accurate but require further evaluation.

HLA DQ2 or DQ8 is present in approximately 25% of the UK population so a

positive test has no predictive value, but a negative test can exclude a

diagnosis of coeliac disease.

2.5.4 Health economics

Published health economics material

A literature review was conducted to identify evidence on the cost-

effectiveness of serological tests for coeliac disease.

Several potentially useful studies were identified (Atkinson et al. 1997;

Dretzke et al. 2004; Dorn et al. 2007; Harewood and Murray 2001; Hopper et

al. 2008; Mein and Ladabaum et al. 2004; Shamir et al. 2006; Spiegel et al.

2004; Swigonski et al. 2008; Yagil et al. 2005). The studies by Atkinson et al.

(1997) and Harewood and Murray (2001) were cost-minimisation studies that

compared serological test strategies with biopsy for diagnosing coeliac

disease. Dorn et al. (2007), Hopper et al. (2008) and Yagil et al. (2005) used

cost-effectiveness analysis to examine the costs and diagnostic accuracy of

serological tests for coeliac disease. Dorn et al. (2007) also examined the cost

effectiveness of HLA testing. Mein and Ladabaum (2004) and Spiegel et

al. (2004) examined the cost effectiveness of testing people with irritable

bowel syndrome for coeliac disease. Shamir et al. (2006) examined a

population screening approach in the adult population and Swigonski et al.

(2008) examined the cost effectiveness of screening for coeliac disease in

children with Downs syndrome, with the specific aim of preventing lymphoma.

None of the 10 papers examining the cost effectiveness of serological tests for

coeliac disease was considered directly applicable to this guideline. However,

one UK study (Dretzke et al. 2004) examined serological tests and used

quality-adjusted life-years (QALYs) as an outcome measure, so was reviewed

in detail for this guideline. The remaining papers were used to explore

previous approaches to modelling serological test strategies and to inform the

structure of the model but were not quality-assessed or reviewed in detail for


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this guideline because they did not include health-related quality-of-life

outcomes and/or were not based in the UK.

A full data extraction form for Dretzke et al. (2004) is available in appendix 6.5

and the techniques from that study (2004) have been examined alongside

careful consideration of the modelling methods used by the other studies

identified in the review.

Summary of Dretzke et al. (2004)

Dretzke et al. (2004) is a full health technology assessment (HTA) of

autoantibody testing in children with newly diagnosed type 1 diabetes. It

includes an economic model to quantify the costs and benefits of screening

for coeliac disease at the time of diagnosis of diabetes. The assessment took

place because of the variation in practice of screening for autoantibodies

associated with coeliac disease in this population.

Six possible screening strategies were compared:

no screening

biopsy of all children

single autoantibody test confirmed by biopsy in those testing positive

combination of autoantibody tests confirmed by biopsy in those testing

positive

single autoantibody test without confirmatory biopsy

combination of autoantibody tests without confirmatory biopsy.

The authors were clear that not all of these strategies are used in current

clinical practice, although all strategies were included for completeness. The

analysis took an NHS perspective, with costs and outcomes modelled over a

lifetime.

The prevalence of undiagnosed coeliac disease in children with diabetes was

estimated from the literature. The effectiveness estimates for the serological

tests were taken from the authors systematic review outlined in the report.

The tests considered were IgA AGA, IgG AGA, IgA EMA, IgA ARA and IgA

tTGA. Other tests were excluded because too few studies were found. The


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values used in the model were taken from the summary ROC curves

presented in the clinical section of Dretzke et al. (2004) for each test at the

point at which sensitivity and specificity were equal. This is called the Q point.

For combination tests the authors assumed that the results of the tests were

independent and clearly set out the method of calculating sensitivity and

specificity for combination strategies. Adherence to a gluten-free diet was

included in the model, as was the proportion of patients who would have

received a later diagnosis through normal clinical routes if they had not been

previously picked up by screening. The delay to diagnosis for these patients

was included, with associated costs and utilities for undiagnosed coeliac

disease. The authors assumed that the delay to diagnosis was 5 years in the

base case.

Utility estimates (quality of life weights) and assumptions were informed by

existing literature. Studies on quality of life of treated and untreated coeliac

disease were searched and reviewed. Utilities could not be derived directly

from the studies identified. Estimates of the utility of treated and untreated

coeliac disease, and of the disutility of endoscopy, biopsy and gluten-free diet

were derived from the literature and assumptions.

Costs were estimated for serological tests, endoscopy and biopsy, and gluten-

free diet. Personal communication was used to evaluate the costs of the

serological tests; this is likely to be because of the absence of a national tariff

for diagnostic tests (such as the British National Formulary for drug prices).

All strategies were compared with a no-screening strategy. The lowest cost

per QALY gained was for a positive IgA EMA with confirmatory biopsy, with anincremental cost-effectiveness ratio of 12,250 per QALY gained compared

with no screening. The least cost-effective strategies were those using IgG

AGA tests alone or in combination with other autoantibody tests. The authors

reported that the results were sensitive to the disutility of being on a gluten-

free diet, the cost of gluten-free diet, the differences in utilities between health

states and the reduction in life expectancy as a result of coeliac disease.


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An important limitation of this study is that the authors do not present the

costs and QALYs separately in the results section. This makes it difficult to

determine whether costs or QALYs have the most influence on the

incremental cost-effectiveness ratio. Limitations of the individual input

parameters are discussed throughout the methods section, but the discussion

does not address limitations of the overall model.

De novo economic model

In summary, there is evidence on the cost effectiveness of serological tests for

various patient populations and country settings; however, there is a lack of

evidence for the cost effectiveness of serological tests for the patient

population of direct relevance to this guideline.

Because of the lack of published economic evidence that fully addresses the

cost effectiveness of serological testing in the decision-making context of this

guideline, the GDG requested the development of a de novo model. Any cost-

effectiveness analysis carried out should also examine the costs and

consequences of the outcomes of diagnosis. Although it is outside the scope

of this guideline to make recommendations on the treatment or management

of coeliac disease, the economic evaluation considers the costs and benefits

of current standard practice after diagnosis of coeliac disease. This allows us

to include the long-term consequences of testing, along with the costs and

consequences of incorrect diagnosis.

A model was developed to estimate the cost effectiveness of serological test

strategies for detecting coeliac disease in patients presenting with signs and

symptoms. The model was built and analysed using TreeAge Pro 2007 Suite(TreeAge software) and adopted a lifetime horizon. Several test strategies

were examined and compared with a no-test strategy (see table 8). The

structure of the decision tree was agreed with the GDG and was also informed

by previous cost-effectiveness studies. Patients accrued costs and utilities

depending on their pathway through the model. At the end of the decision

tree, patients entered a Markov model with states reflecting their eventual

diagnosis (that is, diagnosed as having coeliac disease, no diagnosis of


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coeliac disease or undiagnosed coeliac disease) and picked up costs and

utilities linked with these states until death.

Serological tests examined in the model were the IgA tTGA and the IgA EMA

tests. These were analysed alone and in combination. In all cases, tests were

followed by biopsy to confirm positive results. Strategies with separate IgA

deficiency testing were also included. For completeness a no-test strategy

and a biopsy-only strategy wer

3.-Enfermedad Celiaca

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